Fri Aug 26 2022

85 articles - From Friday Aug 19 2022 to Friday Aug 26 2022

parm_toc.knit

Guidelines

Guidelines, position statements, white papers, technical reviews, consensus statements, etc…


Meta-analysis

meta-analyses and systematic reviews


Original articles

RCT, clinical trials, retrospective studies, etc…

Ann Oncol

Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Pubmed   Journal   ReadQx 

Blood

A novel CD19/CD22/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL.

In addition, tsAb treatment can lead to the long-term elimination of primary B-ALL patient samples in the PDX model and significantly prolong survival. This novel approach provides unique insight into the structural optimization of T-cell-redirected multispecific antibodies using site-specific recombination and may be broadly applicable to heterogeneous and resistant tumor populations as well as solid tumors.

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A Randomized Clinical Trial of the Efficacy and Safety of Rivipansel for Sickle Cell Vaso-occlusive Crisis (VOC).

Timing of rivipansel administration after pain onset may be critical to achieving accelerated resolution of acute VOC. Trial Registration: , NCT02187003 (RESET), NCT02433158 (OLE).

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Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation.

In vitro, azithromycin exposure inhibited T cells cytotoxicity against tumor cells and impaired T cells metabolism through glycolysis inhibition, mitochondrial genes downregulation, and immunomodulatory genes upregulation, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies.

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Dietary methionine starvation impairs acute myeloid leukemia progression.

Finally, we show that inhibition of the H3K36-specific methyltransferase SETD2 phenocopies much of the cytotoxic effects of methionine depletion, providing a more targeted therapeutic approach. In conclusion, we show that methionine depletion is a vulnerability in AML that can be exploited therapeutically, and we provide mechanistic insight into how cells metabolize and recycle methionine.

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Donor natural killer cells trigger production of beta-2-microglobulin to enhance post bone marrow transplant immunity.

Finally, human recombinant B2M increased thymocyte cellularity in a TEC/thymocyte culture system. Our studies uncover a novel therapeutic principle for treating post-transplant immune incompetence and suggest that, upon its translation to the clinic, patients may benefit from adoptive transfer of large numbers of cytokine-activated, ex-vivo expanded donor alloreactive NK-cells.

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Endothelial-leukemia interactions remodel drug responses uncovering T-ALL vulnerabilities.

Lastly, five effective drugs from the two drug screenings were tested in vivo and shown to effectively delay tumor growth/dissemination and prolonging the overall survival (OS). We anticipate that this T-ALL-EC platform can contribute to elucidating leukemia-microenvironment interactions and identify effective compounds and therapeutic vulnerabilities.

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GARP-mediated active TGF-ß1 induces bone marrow NK cell dysfunction in AML patients with early relapse post-allo-HSCT.

Importantly, the blockade of the TGF-ß1 signaling improved the anti-tumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-ß1 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell-based immunotherapy.

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Genomic Profiling for Clinical Decision Making in Lymphoid Neoplasms.

More specifically, their contributions to diagnosis refinement, risk stratification and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses and epigenetic profiling will be discussed, as these will likely become important future tools for implementing precision medicine approaches in clinical decision-making for patients with lymphoid malignancies.

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HbS promotes TLR4-mediated monocyte activation and pro-inflammatory cytokine production in sickle cell disease.

In Townes SCD mice, injection of HbS, unlike HbA, was responsible for an increased production of pro-inflammatory cytokines, which was prevented by the TLR4 inhibitor TAK-242. Our results reveal a novel mechanism of monocyte activation and systemic inflammation in SCD, which opens new promising therapeutic perspectives targeting the HbS-TLR4 interaction.

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Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation.

With transcriptomics, comprehensive imaging, and an in vitro CCM preclinical model this study provides experimental evidence that genes and proteins related to the coagulation cascade affect the brain vasculature and promote neurological side effects such as hypoxia in CCM. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM.

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Leukemia inhibitory factor protects against graft-versus-host disease while preserving graft-versus-leukemia activity.

Mechanistically, rLIF downregulates IL12-p40 expression in recipient dendritic cells (DCs) post irradiation through activating the STAT1 signaling, which results in decreased MHC-II levels on intestinal epithelial cells and reduced donor T cell activation and infiltration. This study reveals a previously unidentified protective role of LIF for GVHD-induced tissue pathology and provides a potential effective therapeutic strategy to limit tissue pathology without compromising anti-leukemic efficacy.

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Location of the t(4;14) translocation breakpoint within the NSD2 gene identifies a subset of high-risk NDMM patients.

These findings have been replicated in an independent replication dataset. Also, univariate and multivariate analysis suggest high-risk markers such as del17p, 1p independently contribute to poor outcome t(4; 14) MM patients.

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Non-canonical EZH2 drives retinoic acid resistance of variant acute promyelocytic leukemias.

Our study provides critical insights into the mechanisms of RA resistance that allow us to eliminate treatment-resistant leukemia cells by targeting EZH2, thus highlighting a potential targeted therapy approach. Beyond RA resistance and APL context, our study also demonstrates the power of single-cell multi-omics to identify, characterize and clear therapy-resistant cells.

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Off-the-shelf cryopreserved platelets for the detection of HIT and VITT antibodies.

Four VITT patient samples tested in the TRA activated PF4-treated but not heparin-treated cryopreserved platelets consistent with recent data suggesting the requirement for PF4-treated platelets for consistent detection. These findings have the potential to transform the testing paradigm in HIT and VITT, making decentralized, technically-simple functional testing available for rapid and accurate in-hospital diagnosis.

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TARGETING FLT3 BY NEW-GENERATION ANTIBODY-DRUG-CONJUGATE IN COMBINATION WITH KINASE INHIBITORS FOR TREATMENT OF AML.

The combination of 20D9-ADC with the TKI midostaurin showed strong synergy in vitro and in vivo, leading to reduction of aggressive AML cells below the detection limit. Our data indicate that targeting FLT3 with an advanced new-generation ADC is a promising and potent antileukemic strategy, especially when combined with FLT3-TKI in FLT3-ITD positive AML.

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The role of iron in chronic inflammatory diseases - from mechanisms to treatment options in Anemia of Inflammation.

The pathophysiology of AI is multifactorial, whereby inflammatory hypoferremia and iron-restricted erythropoiesis play a major role in the context of disease-specific factors. Here we review the recent progress in our understanding of the molecular mechanisms contributing to iron dysregulation in AI, the impact of hypoferremia and anemia on the course of the underlying disease as well as (novel) therapeutic strategies applied to treat AI.

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Blood Adv

Absolute Neutrophil Count by Duffy Status Among Healthy Black and African American Adults.

The Duffy null phenotype is clinically insignificant, but inappropriate reference ranges can propagate systemic racism. Thus, we advocate for development of Duffy null specific ANC reference ranges as well as replacing the term "benign ethnic neutropenia" with Duffy-null associated neutrophil count (DANC).

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Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies.

Importantly, the use of post-transplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germline DDX41-associated myeloid neoplasms (0% vs 53%, p=0.03). Based on these results, we advocate the use of post-transplant cyclophosphamide when individuals with deleterious germline DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.

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Anticoagulation in pediatric cancer-associated venous thromboembolism: a subgroup analysis of EINSTEIN-Jr.

Rivaroxaban exposures were within the adult exposure range despite significant polypharmacy use. The study is registered to as NCT02234843.

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Effects of teclistamab and talquetamab on soluble BCMA levels in patients with relapsed/refractory multiple myeloma.

Baseline sBCMA levels and changes in sBCMA levels at cycle 3 day 1 were similar in patients with high- and standard-risk cytogenetics treated with teclistamab or talquetamab. These results support the use of sBCMA as a potential surrogate marker of tumor burden and treatment response in MM.

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GFAP and NfL increase during neurotoxicity from high baseline levels in pediatric CD19-CAR T-cell patients.

Elevated baseline levels of cGFAP, cNfL and sNfL likely reflect the cumulative injury to the central and peripheral nervous system from prior treatment. However, levels of any of the three biomarkers prior to CAR T cell infusion did not predict ICANS risk.

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Haptoglobin 1 Allele Predicts Higher Serum Haptoglobin and Lower Multiorgan Failure Risk in Sickle Cell Disease.

The HP 1 allele was independently associated with lower risk of developing multiorgan failure during acute chest syndrome (additive model HR 0.5; P<0.001). Future studies assessing the regulation of HP concentrations and ability to bind cell-free hemoglobin according to HP genotype may help to identify SCD patients at high risk for multiorgan failure and to guide interventions, such as rapid initiation of exchange transfusion or HP replacement therapy.

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Therapeutic targeting PRAME with mTCRCAR T cells in acute myeloid leukemia.

Furthermore, the cytolytic activity of PRAME mTCRCAR T cells was enhanced by treating the target cells with IFN-, which increases PRAME antigen expression. These results demonstrate the feasibility and efficacy of targeting PRAME with novel PRAME mTCRCAR T cells.

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Vascular surgery patients with elevated neutrophil lymphocyte ratios have downregulated neutrophil complement RNA expression.

Downregulation of gene expressions of humoral immunity and complement within the neutrophils are associated with elevated NLR. It remains to be determined if and how these changes contribute to increased late mortality previously observed in patients undergoing EVS.

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Blood Cancer J

Myeloma precursor disease (MGUS) among rescue and recovery workers exposed to the World Trade Center disaster.

This study adds to mounting evidence supporting an association between WTC/environmental exposures and MGUS among rescue/recovery workers. Access to MGUS screenings for the entire WTC-exposed cohort could allow for treatment interventions that improve survival.

Pubmed   Journal   ReadQx   PMC

Outcomes of renal transplantation in patients with AL amyloidosis: an international collaboration through The International Kidney and Monoclonal Gammopathy Research Group.

Renal transplantation in selected AL amyloidosis patients is associated with extended overall and renal graft survival. Patients with hematologic CR or VGPR have the most favorable outcomes, and these patients should be considered for renal transplantation.

Pubmed   Journal   ReadQx   PMC

The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation.

The two drugs also cooperated in derepression of transposable elements, more effectively in U937 (mutated TP53) than MOLM-13 (intact TP53), resulting in a "viral mimicry" response. In conclusion, we demonstrate that in vitro and in vivo, the antileukemic and gene-derepressive epigenetic activity of DAC is enhanced by ATRA.

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Haematologica

"ASXL1"-erating inflammation and bone marrow fibrosis in myeloproliferative neoplasms.

Not available.

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ASXL1 mutations accelerate bone marrow fibrosis via EGR1-TNFA axis mediated neoplastic fibrocyte generation in myeloproliferative neoplasms.

Accordingly, combined TNFR antagonist with ruxolitinib significantly reduces fibrocytes production in vitro. Altogether, these findings demonstrate that ASXL1 mutations accelerate fibrocyte production and inflammation in MPNs via EGR1-TNFA axis, providing cellular and molecular basis for BM fibrosis and proof-of-concept for anti-fibrosis treatment.

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In vivo stabilization of a less toxic asparaginase variant leads to a durable anti-tumor response in acute leukemia.

Our results show a comparable long lasting durable anti-leukemic effect between the standard-of-care PEG-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.

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Alpha-beta T and B-cell depleted HLA-haploidentical HSCT in children with myelodysplastic syndromes.

Not available.

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An open-label, phase I/II trial to determine the maximum tolerated dose and investigate safety, pharmacokinetics and efficacy of BI 836858, an unconjugated anti-CD33 monoclonal antibody, in combination with decitabine in patients with acute myeloid leukemia.

Not available.

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BCL6 inhibition ameliorates ruxolitinib resistance in CRLF2-rearranged acute lymphoblastic leukemia.

As a result, FX1 treatment alone had growth-inhibitory and apoptosis-sensitizing effects, but the combination of ruxolitinib and FX1 more potently inhibited leukemia cell growth, enhanced apoptosis sensitivity, and prolonged xenografted mice survival. These findings provide one mechanism for the insufficiency of JAK inhibition for CRLF2-rearranged ALL treatment and BCL6 inhibition as a potentially helpful adjunctive therapy combined with JAK inhibition.

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Bence Jones Island in Shepherd Bay, Ninavut: a little known tribute to the legendary physician and chemist's "thé de voyage".

Rae's report of his voyage in 1855, cited herein, mentioned the island and showed its position on a map of the region. We have located it on a current map of the waterways and landmasses of Nunavut using Google Earth Pro by showing its position at the approximate coordinates of latitude and longitude cited by Rae.

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Characterization of therapy-related acute myeloid leukemia: increasing incidence and prognostic implications.

We conclude that t-AML displays a strong increase in incidence over time and that t-AML constitutes a successively larger proportion of the AML patients. Furthermore, we conclude that t-AML confer a poor prognosis in cytogenetically intermediate and adverse risk, but not in favorable risk AML.

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High transferrin saturation predicts inferior clinical outcomes in patients with MDS.

TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac DFS warrants further study.

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HOXA9/MEIS1 targets in leukemia: reinforced signaling networks and therapeutic opportunities.

Not available.

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Selective inhibition of MCL1 overcomes venetoclax-resistance in a murine model of myelodysplastic syndromes.

While VEN response positively correlated with MDS with excess blasts, al MDS subtypes responded to MCL1 inhibition. Treatment with combined VEN+MCL1 inhibtion was synergistic in al MDS subtypes without significant injury to normal hematopoiesis and reduced MDS engraftment in MISTRG6 mice, supporting the pursuit of clinical trials with combined BCL2+MCL1 inhibition in MDS.

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Serum vascular endothelial growth factor is associated with cardiovascular involvement and response to therapy in Erdheim-Chester disease.

Patients with high sVEGF levels more frequently had cardiac and vascular involvement (58.3% vs 41.4%, p=0.008 and 70.5% vs 48.3%, p=0.0004, respectively). In treatment-naive patients (n=135), the association of CRP > 5 mg/L and sVEGF > 500 pg/mL was strongly associated with vascular involvement (OR 5.54 [2.39-13.62, p.

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Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia.

Our study reports a novel function of SCUBE1 in leukemia and unravels the molecular mechanism of SCUBE1 in MLL-r AML. Thus, SCUBE1 is a potential therapeutic target for treating leukemia caused by MLL rearrangements.

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Structure-function analysis of the role of megakaryoblastic leukemia 1 in megakaryocyte polyploidization.

Not available.

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Under-representation of ethnic minorities in early phase clinical trials for multiple myeloma.

Not available.

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J Hematol Oncol

Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial.

Olverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation.

Pubmed   Journal   ReadQx   PMC

Super-enhancer hijacking LINC01977 promotes malignancy of early-stage lung adenocarcinoma addicted to the canonical TGF-ß/SMAD3 pathway.

TAM2 infiltration induced a rich TGF-ß microenvironment, activating SMAD3 to bind the promoter and the SE of LINC01977, which up-regulated LINC01977 expression. LINC01977 also promoted malignancy via the canonical TGF-ß/SMAD3 pathway. LINC01977 hijacked by SE could be a valuable therapeutic target, especially for the treatment of early-stage LUAD.

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Lancet Haematol

Luspatercept for the treatment of anaemia in non-transfusion-dependent ß-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial.

Interpretation Luspatercept represents a potential treatment for adult patients with non-transfusion-dependent ß-thalassaemia, for whom effective approved treatment options are scarce. Funding Celgene and Acceleron Pharma.

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Mitapivat in adult patients with pyruvate kinase deficiency receiving regular transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial.

Interpretation Mitapivat represents a novel therapy that can reduce transfusion burden in some adults with pyruvate kinase deficiency receiving regular transfusions, and is the first disease-modifying agent approved in this disease. Funding Agios Pharmaceuticals.

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Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial.

Until these trials show a clear benefit, the use of the triple combination in routine practice cannot be recommended. Funding Acerta, AstraZeneca, F Hoffmann-La Roche, and AbbVie.

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Leukemia

Identification of key microRNAs as predictive biomarkers of Nilotinib response in chronic myeloid leukemia: a sub-analysis of the ENESTxtnd clinical trial.

Interestingly, incorporation of NL-CFC output in these panels enhanced predictive performance. Thus, this novel predictive model may be developed into a prognostic tool for use in the clinic.

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Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia.

In mice xenografted with FLT3-ITD+AML cells, co-treatment with oral FLT3 and autophagy inhibitors synergistically impaired leukemia progression and extended overall survival. Our findings identify a molecular mechanism responsible for primary FLT3i treatment resistance and demonstrate the pre-clinical efficacy of a rational combination treatment strategy targeting both FLT3 and autophagy induction.

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Reviews&Editorials

Plenty of the editorials are available as full text through the publisher website using the provided link

Am J Hematol

TKI dosing for chronic phase CML: the case for starting low with dasatinib (50 mg/day) and ponatinib (15 mg/day).

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Blood

CAR-T for follicular lymphoma: are we good to go?

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DDX41: the poster child for familial AML.

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Four decades of progress.

Pubmed   Journal   ReadQx 

Immunosuppressive lung neutrophils.

Pubmed   Journal   ReadQx 

Isn't it ironic: better RBCs by blocking iron.

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Mutant SF3B1 splices a more leukemogenic EVI1.

Pubmed   Journal   ReadQx 

Playing with fire: unrecognized AA genetic predisposition.

Pubmed   Journal   ReadQx 

Rivaroxaban after laparoscopic cancer surgery.

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Ruxolitinib takes center stage for VEXAS syndrome.

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Sounding the alarm for prophylaxis in hTTP.

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uMRD: "the" endpoint or "an" endpoint for CLL?

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Blood Cancer J

Determining drug dose in the era of targeted therapies: playing it (un)safe?

Reduced drug doses may lower toxicity, which in some cases is severe for these agents, and are supported by retrospective studies demonstrating non-inferior outcomes for patients with clinically indicated dose reductions. Here, we review strategies that were used for dose selection in phase I studies of currently approved and select investigational targeted therapies in CLL, and discuss how our initial clinical experience with targeted therapies have pointed to dose reductions, intermittent dosing, and drug combinations as strategies to overcome treatment intolerance and resistance.

Pubmed   Journal   ReadQx   PMC

Haematologica

Lessons learned from therapy-related acute myeloid leukemia.

Not available.

Pubmed   Journal   ReadQx 

Leukemia

Current status and future perspectives in targeted therapy of NPM1-mutated AML.

We also discuss the current therapeutic results obtained in NPM1-mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1-mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.

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Letters&Replies

Letters to the editors and authors’ replies

Am J Hematol

Single-molecule real-time sequencing of the M protein: Toward personalized medicine in monoclonal gammopathies.

Pubmed   Journal   ReadQx 

Blood Cancer J

Outcomes of patients with stage I-II Hodgkin lymphoma who had uniform pre-treatment staging with PET/CT and treatment with limited field radiation therapy after chemotherapy.

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J Hematol Oncol

Revealing the evolution of the tumor immune microenvironment in follicular lymphoma patients progressing within 24 months using single-cell imaging mass cytometry.

Peri-follicular regions function as a barrier by recruiting both CD8 + T cells and immunosuppressive cells, protecting follicular FL-cells from immune attack at diagnosis or POD24. FL-cells reside in a more immune-compromised microenvironment and evade immune cell attacks during POD24. Novel immunotherapeutic approaches harnessing LAG-3, macrophages, and Tregs will be empowered to overcome poor outcomes in patients with FL POD24.

Pubmed   Journal   ReadQx   PMC

Leukemia

Impact of emerging ACA on survival in chronic myeloid leukemia (CML).

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Others

all remaining publications eg case reports, images of the month, etc…

Blood

Atabay EK, Mecca C, Wang Q, et al. Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma. Blood. 2022;139(5):717-731.

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Numerous B cells in a mediastinal mass, but not a B-cell lymphoma.

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Outcomes for adenosine deaminase-deficient SCID.

Pubmed   Journal   ReadQx 

Premature aging of the immune system affects the response to SARS-CoV-2 mRNA vaccine in ß-Thalassemia: additional dose role.

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Splenic diffuse red pulp small B-cell lymphoma with cyclin D3 expression.

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Vats R, Kaminski TW, Ju E-M, et al. P-selectin deficiency promotes liver senescence in sickle cell disease mice. Blood. 2021;137(19):2676-2680.

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Blood Adv

Introduction of an ancient founder glycoprotein VI (GP6) mutation into the Chilean population.

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Longitudinal metabolic study of red blood cells from patients undergoing gender-affirming testosterone therapy.

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More to voxelotor than meets the eye?

Pubmed   Journal   ReadQx 

Practical strategies for creating diversity, equity, inclusion, and access in cancer clinical research: DRIVE.

Pubmed   Journal   ReadQx 

CA Cancer J Clin

Carcinoma of unknown primary: Molecular tumor board-based therapy.

Pubmed   Journal   ReadQx 

Haematologica

Circulating endothelial cells and the study of vascular injury in children undergoing hematopoietic stem cell transplant.

Pubmed   Journal   ReadQx 

Lancet Haematol

Luspatercept in patients with non-transfusion dependent ß-thalassaemia.

Pubmed   Journal   ReadQx 

Mitapivat for treatment of pyruvate kinase deficiency.

Pubmed   Journal   ReadQx 

The evolving multi-agent options for chronic lymphocytic leukaemia treatment.

Pubmed   Journal   ReadQx 

Leukemia

A CRISPR/Cas9 engineered MplS504N mouse model recapitulates human myelofibrosis.

Pubmed   Journal   ReadQx